Peptide YY (PYY) is a peptide consisting of 36 amino acid residues, which is isolated from the porcine upper small intestine. PYY belongs to the pancreatic polypeptide (PP) family together with neuropeptide Y (NPY) isolated from the porcine brain.
It is known that PYY is secreted from the gastrointestinal tract endocrine cell (L cell) along with the diet ingestion, and shows a feeding suppressive action via Y2 receptor. As this action pathways, the intestine-hypothalamus pathway via Y2 receptor of hypothalamic actuate nucleus NPY/AgRP expression nerve cell, and the vagal afferent pathway via Y2 receptor of vagal nerve ending have been reported.
In addition, it has been reported that patients with Anorexia Nervosa (AN) having bad eating behavior show high PYY level in the cerebrospinal fluid, and patients with Bulimia Nervosa (BN) show extremely slow postprandial increase of blood PYY level as compared to that of healthy individuals. Furthermore, it is known that the blood PYY level of obesity patients is lower than that of healthy individuals (Nature, 418, 650-654 (2002), N. Engl. Med., 349, 941-948 (2003) (non-patent documents 1-2)).
On the other hand, the following reports are available.
WO2006/049681 (patent document 1) describes peptide represented by the following formula or a salt thereof.X-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36wherein,X is an N-terminal modifying group;A3 is Ile, Ser or deleted;A4 is Lys or deleted;A5 is Pro or deleted;A6 is Glu, Asp or deleted;A7 is Ala, Asn or deleted;A8 is Pro or deleted;A9 is Gly or deleted;A10 is Glu or deleted;A11, is Asp or deleted;A12 is Ala or deleted;A13 is Ser, Pro or deleted;A14 is Pro, Ala or deleted;A15 is Glu or deleted;A16 is Glu, Asp or deleted;A17 is Leu, Met or deleted;A18 is Asn, Ala or deleted;A19 is Arg or deleted;A20 is Tyr or deleted;A21 is Tyr or deleted;A22 is Ala, Ser or deleted;A23 is Ser, Ala or deleted;A24 is Leu or deleted;A25 is Arg or deleted;A26 is His or deleted;A27 is Tyr or deleted;A28 is Leu, Ile or deleted;A29 is Asn or deleted;A30 is Leu or deleted;A31 is Val, Ile or deleted;A32 is Thr;A33 is Arg;A34 is Gln;A35 is Arg; andA36 is Tyr.
U.S. Pat. No. 5,604,203 (patent document 2) describes a compound represented by the following formula or a pharmacologically acceptable salt thereof.
wherein X is Cys or deleted;each of R1 and R2 is bonded to a nitrogen atom of an α-amino group of the N-terminal amino acid;R1 is H, C1-C12 alkyl, C6-C18 aryl, C1-C12 acyl, C7-C18 aralkyl, or C7-C18 alkaryl;R2 is H, C1-C12 alkyl, C6-C18 aryl, C1-C12 acyl, C7-C18 aralkyl, or C7-C18 alkaryl;A22 is aromatic amino acid, Ala, Aib, Anb, N-Me-Ala, or deleted;A23 is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N-Me-Ala, D-Trp, or deleted;A24 is Leu, Gly, Ile, Val, Tip, Nle, Nva, Aib, Anb, N-Me-Leu, or deleted;A25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH—R (where R is H, a branched or straight chain C1-C10 alkyl group, or an aryl group), Orn, or deleted;A26 is Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrozolylalanine, N-Me-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH—R (R is H, branched chain or straight chain C1-C10 alkyl group, or an aryl group), Orn, or deleted;A27 is Nal, Bip, Pcp, Tic, Trp, Bth, Thi, or Dip;A28 is Leu, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;A29 is Asn, Ala, Gln, Gly, Trp, or N-Me-Asn;A30 is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;A31 is Val, Leu, Ile, Trp, Nle, Nva, Aib, Anb, or N-Me-Val;A32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp;A33 is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH—R (where R is H, branched chain or straight chain C1-C10 alkyl group, or C6-C18 aryl group), or Orn;A34 is Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib, or Anb;A35 is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH—R (where R is H, branched chain or straight chain C1-C10 alkyl group, or C6-C18 aryl group), or Orn;A36 is an aromatic amino acid or Cys;R3 is H, C1-C12 alkyl, C6-C18 aryl, C1-C12 acyl, C7-C18 aralkyl, or C7-C18 alkaryl; andR4 is H, C1-C12 alkyl, C6-C18 aryl, C1-C12 acyl, C7-C18 aralkyl, or C7-C18 alkaryl.
U.S. Pat. No. 6,046,167 (patent document 3) describes the following compound or a pharmaceutically acceptable salt thereof.
N-αR1—[Nle24,28,30, Trp27, Nva31, ψ35/36]PYY(22-36)-NH2,
N-αR1—[Nle24,28, Trp27,30, Nva31, ψ35/36]PYY(22-36)-NH2,
N-αR1—[Nle24,28,30, Phe27, Nva31, ψ35/36]PYY(22-36)-NH2,
N-αR1—[Nle24,28, Phe27, Trp30, Nva31, ψ35/36]PYY(22-36)-NH2,
N-α-R1—[Trp30, ψ35/36]PYY(25-36)-NH2,
N-α-R1—[Trp30]PYY(25-36)-NH2,
N-α-R1—[Nle24,28, Trp30, Nva31, ψ35/36]PYY(22-36)-NH2 and
N-α-R1—[Nle28, Trp30, Nva31, ψ35/36]PYY(22-36)-NH2,
wherein
R1 is H, (C1-C12)alkyl or (C1-C12)acyl;
Ψ is a pseudopeptide bond selected from the group consisting of —CH2—NH—, —CH2—S—, —CH2—CH2—, —CH2—O—, and —CH2—CO—.
WO2004/056314 (patent document 4) describes “a transmucosal Y2 receptor-binding peptide formulation capable of raising the concentration of the Y2 receptor-binding peptide in the plasma of a mammal by at least 5 pmoles per liter of plasma or more when a dose containing at least 50 μg of the Y2 receptor-binding agonist is administered transmucosally to said mammal”.
WO2005/080433 (patent document 5) describes “a pharmaceutical composition product comprising: a. an aqueous solution formulation of a Y2 receptor binding compound at a concentration sufficient to produce therapeutically effective plasma concentrations and; b. an actuator able to produce an aerosol of said solution, wherein the spray pattern ellipticity ratio of said aerosol is between 1.00 and 1.40 when measured at a height of between 0.5 cm and 10 cm distance from the actuator tip”.
WO2006/007412 (patent document 6) describes “an aqueous Y2 receptor-binding peptide formulation suitable for transmucosal administration, comprising a Y2 receptor-binding peptide, a cyclodextrin and an effective amount of an anti-microbial preservative”.
US2008/0194486 (patent document 7) describes “a compound comprising a PYY peptide or a functional derivative thereof which is coupled to a reactive group, said reactive group being capable of reacting with an amino group, a hydroxyl group or a thiol group on a blood component so as to form a stable covalent bond therewith, thereby substantially preventing said PYY peptide or functional derivative thereof from crossing the blood brain barrier”.